TY  - JOUR
AU  - Schäker, Kathrin
AU  - Bartsch, Susanne
AU  - Patry, Christian
AU  - Stoll, Sandra J
AU  - Hillebrands, Jan-Luuk
AU  - Wieland, Thomas
AU  - Kroll, Jens
TI  - The bipartite rac1 Guanine nucleotide exchange factor engulfment and cell motility 1/dedicator of cytokinesis 180 (elmo1/dock180) protects endothelial cells from apoptosis in blood vessel development.
JO  - The journal of biological chemistry
VL  - 290
IS  - 10
SN  - 1083-351X
CY  - Bethesda, Md.
PB  - Soc.
M1  - DKFZ-2017-03471
SP  - 6408 - 6418
PY  - 2015
AB  - Engulfment and cell motility 1/dedicator of cytokinesis 180 (Elmo1/Dock180) is a bipartite guanine nucleotide exchange factor for the monomeric GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1). Elmo1/Dock180 regulates Rac1 activity in a specific spatiotemporal manner in endothelial cells (ECs) during zebrafish development and acts downstream of the Netrin-1/Unc5-homolog B (Unc5B) signaling cascade. However, mechanistic details on the pathways by which Elmo1/Dock180 regulates endothelial function and vascular development remained elusive. In this study, we aimed to analyze the vascular function of Elmo1 and Dock180 in human ECs and during vascular development in zebrafish embryos. In vitro overexpression of Elmo1 and Dock180 in ECs reduced caspase-3/7 activity and annexin V-positive cell number upon induction of apoptosis. This protective effect of Elmo1 and Dock180 is mediated by activation of Rac1, p21-activated kinase (PAK) and AKT/protein kinase B (AKT) signaling. In zebrafish, Elmo1 and Dock180 overexpression reduced the total apoptotic cell and apoptotic EC number and promoted the formation of blood vessels during embryogenesis. In conclusion, Elmo1 and Dock180 protect ECs from apoptosis by the activation of the Rac1/PAK/AKT signaling cascade in vitro and in vivo. Thus, Elmo1 and Dock180 facilitate blood vessel formation by stabilization of the endothelium during angiogenesis.
KW  - Adaptor Proteins, Signal Transducing (NLM Chemicals)
KW  - DOCK1 protein, human (NLM Chemicals)
KW  - ELMO1 protein, human (NLM Chemicals)
KW  - Guanine Nucleotide Exchange Factors (NLM Chemicals)
KW  - RAC1 protein, human (NLM Chemicals)
KW  - rac GTP-Binding Proteins (NLM Chemicals)
KW  - rac1 GTP-Binding Protein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25586182
C2  - pmc:PMC4358276
DO  - DOI:10.1074/jbc.M114.633701
UR  - https://inrepo02.dkfz.de/record/127448
ER  -